Process of making an aqueous calcium carbonate suspension

ABSTRACT

The present invention relates to a high dosage calcium carbonate aqueous antacid pharmaceutical suspension for oral use, and methods of preparation.

This application is the §371 mational stage entry of PCT/US99/04652,filed Mar. 11, 1999 which claims the benefit of priority fromprovisional application No. 60/077,659, filed Mar. 11, 1998.

FIELD OF THE INVENTION

The invention relates to a novel process of making liquid antacidcalcium carbonate containing compositions for neutralizing stomach acid(and calcium source or calcium nutritional supplement) in humans andother animals.

BACKGROUND OF THE INVENTION

Liquid pharmaceutical compositions for delivery of an antacid aregenerally of the suspension form. They constitute a finely dividedantacid active, in solid form which is suspended in a liquid medium.These compositions generally are alkaline, with typical pH values in therange of 7.5 to 8.7.

One problem faced by such liquid compositions is that the pH may drifteither below or over the 7.5 to 8.7 pH limits due to equilibrium notbeing established within 24 hours between the carbonate salt and itsenvironment. This results in such things as color changes if a pHsensitive dye is used, possible microbial growth, and acceleration ofbase catalyzed degradations.

One method which has been used to stabilize such a suspension isdescribed in U.S. Pat. No 5,498,426, Wilson et al., which includes analkali metal phosphate salt, and alkali metal bicarbonate salt inaddition to the alkaline earth carbonate salt.

Another group of patents to Beyerle et al., U.S. Pat. No. 5,631,026 andU.S. Pat. No. 5,455,050 include with the calcium carbonate a magnesiumcarbonate and/or magnesium trisilcate as well as a carboxylic acid pHadjusting agent.

U.S. Pat. No. 5,002,777 discloses a concentrated suspension of calciumcarbonate in a liquid carrier contained in a capsule, in which theliquid carrier is PEG 400.

The problem faced by the pH drift has not been successfully solved forliquid antacid compositions which are magnesium or aluminum free. Thepresent invention is the recognition of this problem and a solution tosuch whereby a pleasant liquid antacid formulation is achieved which ispH stable.

SUMMARY OF THE INVENTION

The present invention is to a process of making an aluminum andmagnesium free liquid antacid formulation which is stable at a pH fromabout 7.5 to about 8.7. The liquid antacid formulation is also free fromantimicrobial contamination during the stable shelf life of the product.

The aluminum and magnesium free antacid formulation is a calciumcarbonate aqueous antacid suspension having a pH of about 7.5 to about8.7, which suspension is prepared by a process which comprises the stepsof:

a) adding to water an effective amount of particulate calcium carbonatewith mixing until the particulate is completely wetted and dispersed;and

b) adding to said mixture of part a) with stirring an amount of asuspending agent for a time sufficient to substantially coat saidparticulate material, and to produce a suspension; or alternately addingb) to a) and;

c) while stirring, titrating the suspension of part b) with a pHadjusting agent to provide a pH of about 6.4 to 7.0 to the aqueousantacid suspension.

The present invention is also directed to a liquid antacidpharmaceutical formulation for neutralizing excess stomach acid. Thepresent invention is also a method of orally administering to a mammalin need of such treatment an effective amount of said liquid antacidcomposition.

DETAILED DESCRIPTION OF THE INVENTION

The aqueous suspensions of the present invention have been found to be astabilized liquid calcium carbonate containing antacid having a pH rangeof about 7.5 to about 8.7, meeting USP standards. The suspensions ofthis invention have been found to be stable with regard toantimicrobial, viscosity, defoaming, and acid neutralizing capacity(ANC) parameters, as well as to pH. The present invention has found thatthe selective order of addition and mixing of the essential componentsherein provides the stable pH of this suspension and further providesfor the formation of a higher concentrated suspension of calciumcarbonate than previously available to the marketplace. The higher doseformulation of liquid calcium carbonate, in addition to providingmaximum acid neutralizing capacity, may also provide a 1000 mg ofcalcium per dosage to a mammal in need of such calcium for buildingbone, for treatment of osteoporosis, for pre-menstrual syndrome, etc.

The present invention is to an aqueous antacid suspension for oral usehaving a pH of about 7.5 to about 8.7 of calcium carbonate, prepared bya process which comprises:

a) adding to water an effective amount of calcium carbonate with mixinguntil the calcium carbonate is completely wetted and dispersed; and

b) adding to said mixture of part a) with stirring a suspending agentfor a time sufficient to substantially coat said carbonate, and toproduce a suspension; alternatively, the suspending agent may be addedto water first, and calcium carbonate adding second; and

c) while stirring, titrating the suspension of part b) with a pHadjusting agent to provide a pH of about 6.4 to about 7.0 to the aqueousantacid suspension.

Suitable use of a thickening or suspending agents includes but is notlimited to those generally used in aqueous antacid formulations, forexample, microcrystalline cellulose, such as Avicel, xanthan gum, guargum, methyl celluloses such as HPMC and sodium carboxymethylcellulose.Preferably, two suspending agents are used, Avicel and xanthan gum.

An appropriate wetting agent, such as glycerin may be utilized to insuremaximum dispersion of the thickening agent in the aqueous system. Tosuch end, the thickening agent, such as xanthan gum is preferablyadmixed with glycerin in a separate container prior to addition to thesuspension/mixture. An alternative to the thickening agent/glycerinpremix is the use of appropriate mechanical dispersing means, such as ahigh shear mixer to assist dispersion of the thickening agent. Acommercially available readily dispersible thickening agents may also beused, such as KELTROL RD brand of readily dispersible xanthan gum fromKelco, division of Merck. Such readily dispersible thickening agents mayprovide adequate dispersion upon direct addition to the aqueous system.

Previous calcium carbonate liquid antacid suspensions have been found tobe unstable, and have been found to have to high a resulting pH level.The pH level of the present invention is within the USP standards as hasbeen found to be stable, and can be maintained with an efficientpreservative system. Accordingly, a pH adjusting agent is a necessarycomponent of the invention. Citric acid has been found to be a preferredpH adjusting agent, although other carboxylic acids such as tartaric,adipic, benzoic, carbonic, cinnamic, fumaric, glutaric, gluconic,hydroxybenzoic, malonic, malic, phthalic, oxalic, sorbic, succinic andthe like may be utilized. The amount of pH adjusting agent should besufficient to bring about, and maintain the pH of the final product in arange of 7.5 to about 8.7. In general from about 0. 025 to about 0.2%w/w of the pH adjusting agent has been found suitable. As the pHadjusting agent is added at the last step, while mixing, the titrate ofthe suspension with the pH adjusting agent will be added in an amountsufficient to provide a pH of about 6.4 to 7.0 of the aqueous antacidsuspension. It is critical that the pH is measured within 15 minutesafter the pH adjusting agent is added. The resulting suspension the nextday should have equilibrated to the final desired pH range of from about7.5 to about 8.7.

Any desired pharmaceutically acceptable adjuvant may be added. Forexamples, one or more preservatives, such as benzyl alcohol; flavouringagents, such as oil of orange, imitation wintergreen flavour, lemon-limeflavors, mint flavors, or combinations thereof; sorbitol serves toincrease shelf life and palatability; wetting agents, an antiflatuentwhich is preferably simethicone, preferably in an antiflatuent amount offrom about 0.1 to about 2.0% w/w is suitable; sweetening agents, such ascalcium sacccharin; colouring agents; taste enhancing agents, such ascalcium choride; and tetrapotassium pyrophosphate.

A unique aspect of the present invention is the order in which theessential buffering component must be admixed in order to the finalsuspension to achieve the desired pH range. If the pH adjusting agent isadded to the active antacids prior to the last step, it tends to achievea higher pH or an unstable suspension. It is therefore, critical thatall of the components, but for the buffering, be added to the suspensionand thoroughly dispersed with the gums prior to the addition of the pHadjusting agent.

A process which combines tetrapotassium pyrophosphate and citric Acid inone solution, at the same time, has a resulting pH which is inconsistentas it can either be below or over the 7.5 to 8.7 limit and takes about30 days to equilibrate.

In a preferred embodiment, there are a number of separate phases ofingredients which are premixed prior to addition of the liquid antacidsuspension. By this is meant, a calcium chloride phase, an firstsuspending agent phase, a second suspending agent phase, a sweeteningphase, an the pH adjusting agent phase. Each individual component isadmixed with a formula amount of water and held as a separate phaseuntil addition to the preparation vessel.

While the order of addition to the preparation vessel is thepreservative phase followed by the calcium chloride phase, either orderis acceptable. To this mixture is added the first suspending agent, suchas the Avicel premix, with continual mixing, until the batch becomessmooth and uniform, with no lumps. With continued mixing, the powderedcalcium carbonate, USP is mixed. The suspension is stirred until thecalcium carbonate is uniformly dispersed and thoroughly coated. To thissuspension mixture is added, preferably while stirring is maintained,the second suspending agent, which is preferably xanthan gum. In apreferred aspect the xanthan gum is premixed, not with water but withglycerin. The resulting batch mixture is continued to be stirred untilthe xanthan gum is adequately hydrated.

To this batch mixture is added the sorbitol solution, USP admixed withformula amounts of water and continued stirring until the batch isuniform. If an antiflatulent, or any other suitable biologically activeagents are desired to be added to the suspension, they are added at thisstage until the batch is uniform.

While continued mixing, the sweetening phase is added and with continuedstirring until uniform. While mixing the optional flavouring agents arealso added. Again, the order of addition of these excipients isvariable, and may be added at any step herein, a preferred embodimentbeing in this explicit order. At this time, it is preferred that a batchpH be taken. To this admixture is added the buffering agent phase withan additional formula water. The batch is slowly mixed until uniform. Abatch pH is again (or first taken) at this step in the process. To thisbatch, the pH adjusting phase is now titrated. The Citric Acid Phase istitrated to a target pH of about 6.4 to 7.0. The pH is measured within15 minutes after the pH adjusting agent is added.

As a guideline, the citric acid phase (CAP) is administered inaccordance with the batch pH of the mixture prior to addition of theCAP. If the batch pH before CAP titration is equal to or greater than7.5, approximately 0.2625% w/w CAP (equivalent to 0.075% w/w CitricAcid) is added, and if necessary more CAP is added in 0.0875% w/wincrements (equivalent to 0.025% w/w Citric Acid), until the target pHis reached. The batch is mixed until uniform, or approximately 15minutes. The pH is measured within 15 minutes after each increment.

If the batch pH before CAP titration is equal to or less than 7.5,approximately 0.0875% w/w CAP (equivalent to 0.025% w/w Citric Acid) isadded, and if necessary more CAP is added in increments of 0.0875% w/wCAP until the target pH is reached. The batch is mixed until uniform, orapproximately 15 minutes. The pH is measured after each increment.

While not dispositive of the effects of calcium carbonate solubility asit applies to the pH problem for stabilization of liquid antacidsuspensions, the following has been observed:

That the reactions associated with calcium carbonate solubility in waterare a combination of:

CaC(O)₃(solid)⇄Hydration⇄CaC(O)₃(hydrate)+H₂O+C(O)₂⇄Ca(HCO₃)₂⇄Ca⁺⁺+HCO₃−

CaC(O)₃(hydrate)⇄Ca⁺⁺+CO₃−

H₂O+C(O)₂⇄H₃O⁺+HCO₃−

The hydration step is the rate limiting step for dissolution.

The solubility of calcium carbonate is about 0.05-0.07% mg/ml at roomtemperature. The pH of a 10% dispersion of calcium carbonate in water(saturated solution) is about 9.0.

The solubility of calcium carbonate is increased by an increase incarbon dioxide solubilized in the water. The solubility of calciumcarbonate decreases with increasing temperatures. The rate of agitationinfluences the rate of solubility of calcium carbonate. It could take upto 5 days for the saturated solution of calcium carbonate in water to beformed. It takes less than one day if air (carbon dioxide) is passedthrough the mixture prior to stirring.

Phosphates and anionic surfactants sequester calcium increasing both therate and extent of solubilization of calcium carbonate. However, somephosphates adhere to the calcium carbonate particle surface inhibitingthe sequestration.

Based upon this information, and the assumption that the pH change inthe calcium carbonate liquid suspension is due solely to the rate ofsolubilization of calcium carbonate, the CAP should be added after thesaturated solution of calcium carbonate is formed. Theemulsifier/texturizer with buffering properties, in this case,tetrapotassium pyrophosphate, could be added first with time need toreach a constant pH. Once the constant pH is reached after the phosphateaddition, the pH adjusting agent, CAP, could be added to adjust the pHto a lower USP limit.

Another aspect of the present invention is a stable, high dosage calciumcarbonate aqueous antacid formulation which comprises:

Avicel NF 0.52 Calcium Carbonate, USP 17.47 Glycerin, NF 5.00 XanthanGum, NF 0.28 Sorbitol, USP 10.00 Citric Acid Anhydrous, USP* 0.025 to0.20 Water, USP qs 100% w/w

Another aspect of the present invention is the stable, high dosagecalcium carbonate and simethicone containing aqueous antacid formulationwhich comprises:

Avicel NF 0.52% w/w Calcium Carbonate, USP 17.47 Glycerin, NF 5.00Xanthan Gum, NF 0.28 Sorbitol, USP 10.00 Simethicone, USP, 30% 1.75Flavouring agent 1.05 Citric Acid Anhydrous, USP* 0.20 Water, USP q.s.100

Another aspect of the present invention is a method for neutralizingexcess stomach acid in a mammal in need thereof, which method comprisesorally administering to said mammal an effective amount of a liquidantacid suspension as noted above.

The invention will now be described by reference to the followingexamples which are merely illustrative and are not to be construed as alimitation of the scope of the present invention.

EXAMPLE 1

The following phases are prepared, not necessarily in the followingorder. Each phase may be prepared concurrent with or immediately beforeadding to the main batch in the preparation vessel.

The xanthan gum phase is prepared by dispersing the gum in glycerin. TheAvicel gum is prepared by dispersing in water. The calcium chloridephase, the calcium saccharin phase, the tetrapotassium pyrophosphatephase, and the citric acid phase are prepared by dissolving each phasecomponent in water.

The main batch is prepared by charging water into the Mixing Tank,followed by the addition of Benzyl Alcohol, Calcium Chloride Phase,Avicel Gum Phase, Calcium Carbonate, Xanthan Gum Phase, Simethicone,Calcium Saccharin Phase, Flavouring Agent(s), and optionally theTetrapotassium Pyrophosphate phase. The addition to the main batch maybe in any order provided that the batch is uniform, dispersed and thecalcium carbonate well coated, prior to the addition of the CAP phase.The batch pH is adjusted to a target of about 6.4 using the CAP. Thefinal batch pH is measured after one day.

INGREDIENTS AMOUNTS % W/W Water, USP 65.34 Benzyl Alcohol, NF 0.75Calcium Chloride, USP 0.12 Avicel NF 0.52 Calcium Carbonate, USP 17.47Glycerin, NF 5.00 Xanthan Gum, NF 0.28 Sorbitol, USP 10.00 CalciumSaccharin, USP 0.10 Flavour(s) 1.43 Tetrapotassium Pyrophosphate, FCC0.08 Citric Acid Anhydrous, USP* 0.200 *Actual amount used can varybetween 0.025 and 0.20 w/w depending upon titration pH. The citric acidUSP in the formula is used to adjust the batch pH to a target pH ofabout 6.4 to 7.0.

Each 5 ml contains 1000 mg Calcium Carbonate.

The Calcium Chloride Phase is made by admixing, Water, USP 1.00% w/w andCalcium Chloride 0.12% w/w.

The Avicel Gum Phase is made by admixing Water, USP 21.00% w/w andAvicel 0.52% w/w.

The Xanthan Gum Phase is made by admixing Glycerin, NF 4.50% w/w andXanthan Gum, 0.28% w/w.

The Calcium Saccharin Phase is made by admixing Water, USP, 1.0% w/w andCalcium saccharin 0.10% w/w.

The Tetrapotassium Pyrophosphate Phase is made by admixing Water, USP1.00% w/w and tetrapotasium pyrophosphate, FCC 0.080% w/w.

The Citric Acid Phase is made by admixing Water, USP 0.50% w/w to Citricacid USP 0.20% w/w.

EXAMPLE 2

As above, the phases are prepared, not necessarily in a particularorder. Each phase may be prepared concurrent with or immediately beforeadding to the main batch in the preparation vessel.

Also, as above, the addition to the main batch may be in any order ofeach of the components, provided that the batch is uniform, dispersedand the calcium carbonate well coated, prior to the addition of the CAPphase. The batch pH is adjusted to a target of about 6.4 to 7.0 usingthe CAP. The final batch pH is measured after one day.

INGREDIENTS AMOUNTS % W/W Water, USP 63.63 Benzyl Alcohol, NF 0.75Calcium Chloride, USP 0.12 Avicel NF 0.52 Calcium Carbonate, USP 17.47Glycerin, NF 5.00 Xanthan Gum, NF 0.28 Sorbitol, USP 10.00 CalciumSaccharin, USP 0.10 Simethicone, USP, 30% 1.75 Flavour 1.05Tetrapotassium Pyrophosphate, FCC 0.08 Citric Acid Anhydrous, USP* 0.20*Actual amount used can vary between 0.025 and 0.20 w/w depending upontitration pH. The citric acid USP in the formula is used to adjust thebatch pH to a target pH of about 6.4 to 7.0.

Each 5 ml contains lOOOmg Calcium Carbonate and 30 mg Simethicone

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

The above description fully discloses the invention including preferredembodiments thereof Modifications and improvements of the embodimentsspecifically disclosed herein are within the scope of the followingclaims. Without further elaboration, it is believed that one skilled inthe are can, using the preceding description, utilize the presentinvention to its fullest extent. Therefore the Examples herein are to beconstrued as merely illustrative and not a limitation of the scope ofthe present invention in any way. The embodiments of the invention inwhich an exclusive property or privilege is claimed are defined asfollows.

What is claimed is:
 1. A method for neutrallizing excess stomach acid ina mammal in need thereof, which method comprises orally administering tosaid mammal an effective amount of a liquid antacid suspension having aformula comprising: Avicel NF 0.52 Calcium Carbonate, USP 17.47Glycerin, NF 5.00 Xanthan Gum, NF 0.28 Sorbitol, USP 10.00 Citric AcidAnhydrous, USP 0.025 to 0.20 Water, USP q.s. 100% w/w.


2. A method for neutralizing excess stomach acid in a mammal in needthereof, which method comprises orally administering to said mammal aneffective amount of a liquid antacid sispension of the formulacomprising: Avicel NF 0.52 Calcium Carbonate, USP 17.47 Glycerin, NF5.00 Xanthan Gum, NF 0.28 Sorbitol, USP 10.00 Simethicone, USP, 30% 1.75Flavouring agent 1.05 Citric Acid Anhydrous, USP 0.20 Water, USP q.s.100% w/w.


3. A method of preparing a stable aqueous antacid suspension for oraluse with a pH of about 7.5 to about 8.7 which comprises: a) adding towater an effective amount of calcium carbonate with mixing until thecalcium carbonate is completely wetted and dispersed; and b) adding tosaid mixture of part a) with stirring a suspending agent for a timesufficient to substantially coat said calcium carbonate, and to producea suspension; or alternately adding b) to a); c) while stirring,titrating the suspension of part b) with a pH adjusting agent to providea pH of about 6.4 to 7.0 to the aqueous antacid suspension; and d) uponstanding the suspension will equilibrate to a stable pH of about 7.5 to8.7.
 4. The suspension according to claim 3 wherein the suspending agentof part b) is first added to water prior to the addition of the calciumcarbonate.
 5. The suspension according to claim 4 wherein the suspendingagent is comprised of two different agents, and the first suspendingagent is microcrystalline cellulose.
 6. The suspension according toclaim 5 wherein the second suspending agent is xanthan gum.
 7. Thesuspension according to claim 6 wherein the xanthan gum is admixed withglycerin prior to adding to the suspension.
 8. The suspension accordingto claim 3 wherein the pH adjusting agent is citric acid.
 9. Thesuspension according to claim 8 wherein the citric acid in water istitrated to the suspension of part (b) on the basis of batch testing ofthe suspension wherein the batch pH is greater or less than a pH of 7.5.10. The method according to claim 3 which further comprises the additionof a flavouring agent to the suspension.
 11. The method according toclaim 3 which further comprises the addition of an effective amount ofan antiflatuent which is simethicone to the suspension.
 12. The methodaccording to claim 3 which further comprises the addition of bothsorbital and a sweetening agent to the suspension.
 13. The methodaccording to claim 3 which further comprises the addition oftetrapotassium pyrophosphate to the suspension.
 14. The method accordingto claim 3 wherein the calcium carbonate is from about 1.5 to about20.0% w/w.